Global Management of Antimicrobial Resistance
97039 - GLOBAL HEALTH, ANTIMICROBIAL DRUGS AND VACCINES
Russell E. Lewis, Associate Professor, Infectious Diseases
11/1/2022
Overview
Until the 20th Century, influenza, pneumonia, tuberculosis, and diarrhea/enteric diseases were the top three causes of death in Western countries. The average life expectancy of adults was less than 50 years, and 2% of children failed to live beyond age 5 years with most deaths caused by communicable diseases.
Industrialization and growing wealth in the 19th century brought improvements in sanitation and drinking water, leading to dramatic improvements in life expectancy. By the early 20th century, vaccination was becoming established for many preventable infectious diseases, including vaccines for pertussis, diptheria, yellow fever and tuberculosis. However, life-threatening bacterial infections remained a common threat. Strep throat was sometimes a fatal infection, ear infections could lead deafness, mastoiditis or meningitis with a 90% mortality rate, and surgery or childbirth was much more dangerous.
Figure 1. Changes in life expectancy over 500 years
The microbiologist Paul Ehrlich (1854-1915) is generally credited with the first discovery and medical application of a synthetic drug (arsphenamine or Salvarsan) for the treatment of syphilis. The term “antibiotic” was later introduced by in 1943 by Selman Waksman-the discoverer of streptomycin and the first effective antibiotic for tuberculosis. Erlich’s approach of screening libraries of chemicals for selective antimicrobial properties formed the basis of early antibiotic research and led to the discovery of the first sulfa antibiotics (e.g., sulfamidochrysoidine, sulfanilamide) that are still in clinical use today.
The serendipitous discovery of penicillin on September 3, 1928 by Alexander Fleming, and its subsequent purification of the drug in quantities needed for clinical testing by Florey and Chain in the late 1930s, was a major breakthrough in establishing the clinical efficacy of antibiotics for common bacterial infections. Alexander Fleming was also among the first physicians to caution about the risks of resistance to penicillin if used too little or for a too short of period during treatment.
It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body. The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily under-dose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant. -Sir Alexander Fleming
Fleming’s predictions were proven to be true within a couple of years, with the first cases of penicillin resistance reported in 1947. Thus the “arms race” between antimicrobial resistance and the discovery of new antibiotics to treat new pathogens with new forms of antibiotic resistance began.
Although resistant infections were frequently encountered in the early days of antibiotic use, a flow of new antibiotics from 1950s-1980’s provided alternative treatments. For many forms of clinically-encountered resistance, It was possible to simply switch treatment once resistance against a specific antibiotic became a major problem. But then the antibiotic discovery began to slow. The latest discovery of a new antibiotic class that has reached the market was in 1987. Since then, there has been a lack of innovation in the field, and today there are few novel antibiotic classes in the drug pipeline. In Module 2 we will examine the scientific challenges and market forces that have made new antibiotic discovery increasingly difficult in both in both developed and low-middle-income countries (LMICs)
Once resistance has developed in a bacteria, it can spread from a colonised patient to another patient if appropriate hygienic precautions (e.g., hand hygiene, isolation) are not taken. The risk of resistant bacteria spreading is enhanced in crowded environments, especially when people in the surrounding area are receiving antibiotics - a common situation in hospitals and other healthcare facilities.
The consequences of faltering antibiotic discovery are now seen worldwide as more and more bacterial infections are becoming hard to treat once again. Especially worrisome is the lack of antibiotics against Gram-negative bacteria. The rapid global spread of multi- and pan-resistant bacteria (also known in the lay press as “superbugs”) can cause infections that are not treatable with existing antibiotics.
Figure 2. Antibiotic discovery timeline
Recognizing the growing global threat of antibiotic resistance (AMR) on human health but also the economy and human development, in 2017 The World Health Organization (WHO) developed a Global Action Plan on AMR. The plan outlines 21 strategies and 5 strategic objectives action plans that should be implemented in member states to address AMR.
- Improvements in the awareness and understanding of antimicrobial resistance through effective communication, education and training
- Strengthening of knowledge and evidence base of AMR through surveillance and research
- Reductions in the incidence of infection through effective sanitation, hygiene and infection prevention measures
- Optimization the use of antimicrobial medicines in human and animal health
- Development the economic case for sustainable investment that takes account of the needs of all countries, and increase investment in new medicines, diagnostic tools, vaccines and other interventions
The WHO also published a Priority Pathogen List for research and development of new antibiotics. This priority list includes bacterial pathogens that are considered to be be the biggest threat to human health beyond Mycobacterium tuberculosis,, which was previously listed as health priority pathogen for which innovative new treatments are urgently needed. The WHO list breaks down pathogens into three groups:
| Priority group | Pathogens included |
|---|---|
| Critical | Acinetobacter baumannii (Carbapenem-resistant) Pseudomonas aeruginosa (Carbapenem-resistant) Enterbacterales (3rd generation cephalosporin, carbapenem-resistant) |
| High | Enterococcus faecium, vancomycin-resistant Staphylococcus aureus, methicillin-resistant, vancomycin intermediate and resistant Helicobacter pylori, clarithromycin-resistant Campylobacter, fluoroquinolone-resistant Salmonella spp., fluoroquinolone-resistant Neisseria gonorrhoeae, 3rd generation cephalosporin-resistant, fluoroquinolone-resistant |
| Medium | Streptococcus pneumoniae, penicillin-non-susceptible Haemophilus influenzae, ampicillin-resistant Shigella spp., fluoroquinolone-resistant |
Situation in Italy
Southern Europe, including Italy, has among the highest currently reported resistance rates among pathogens on the WHO “critical pathogens” list. For example, surveillance data from the European Centres for Disease Control (ECDC) have reported a dramatic increase in carbapenem-resistance in Italy since 2009, with now more than one-third of Klebsiella pneumoniae resistant to previously-considered last-line antibiotics such as carbapenems. (see link to interactive resistance atlas here) Similarly, the The Italian [Micronet Resistance Surveillance] program (https://www.epicentro.iss.it/antibiotico-resistenza/epidemiologia-italia) has reported:
- 26.4% of Escherichia coli are resistant to 3rd generation cephalosporins
- 29.5% of Klebsiella pneumoniae are resistant to carbapenems (including 33.1% resistant to multiple drug classes)
- 15.9% of Pseudomonas aeruginosa are resistant to carbapenemase
- 80.8% of Acinetobacter spp. are resistant to carbapenems with 78.8% of species resistant to multiple drug classes
- For Staphylococcus aureus , the percentage of methicillin-resistant isolates (MRSA) remained stable, around 34%, while a worrying trend continues to increase in the percentage of Enterococcus faecium isolates resistant to vancomycin, which in 2020 was equal at 23.6%
- For Streptococcus pneumoniae there was a slight increase in both the percentage of isolates resistant to penicillin (13.6%) and those resistant to erythromycin (24.5%).
- Overall, higher antimicrobial resistance rates (around 40%) are observed in ICUs versus general medical wards for both carbapenem-resistant K. pneumoniae and methicillin-resistant S. aureus.
Figure 3. Regional difference in CRE bloodstream infection incidence per 100,000 residents in Italy. Source:Micronet https://www.epicentro.iss.it/antibiotico-resistenza/cre-dati
In 2017, a report by the the ECDC noted that the AMR situation in Italian hospitals and regions poses a major public health threat to the country. The levels of carbapenem-resistant Enterobacteriaceae (Enterobacterales) (CRE) and Acinetobacter baumannii have now reached hyper-endemic levels in many hospitals, and together with increasing methicillin-resistance among the Gram-positive species Staphylococcus aureus (MRSA) has fueled Italy’s ranking as one of the Member States with one of the highest level of antibiotic resistance in Europe. Factors noted by the ECDC that contribute negatively to the poor control of antibiotic resistance in Italy include:
- Little sense of urgency about the current AMR situation from most stakeholders and a tendency by many stakeholders to avoid taking charge of the problem
- Lack of institutional support at national, regional and local level
- Lack of professional leadership at each level
- Lack of accountability at each level
- Lack of coordination of the activities between and within levels.
The future
- Drug-resistant diseases already cause at least 700,000 deaths globally a year, including 230,000 deaths from multidrug-resistant tuberculosis, a figure that could increase to 10 million deaths globally per year by 2050 under current projections if no action is taken. In India, antibiotic-resistant neonatal infections cause the deaths of nearly 60,000 new-borns each year Around 2.4 million people could die in high income countries between 2015 and 2050 without a sustained effort to contain antimicrobial resistance.
- Increasing resistance could lead to an unthinkable future of untreatable infections, reversing more than a 100 years of medical progress. Routine medical procedures or surgery become much more dangerous and associated with higher complication rates. Immunosuppression, cancer chemotherapy and transplantations may become associated with unacceptable risk for many patients if infections cannot be effectively prevented and treated.
- Economic and social progress in many countries will be dramatically impacted leading to political and social instability. The economic damage of uncontrolled antimicrobial resistance will be comparable to the shocks experienced during the 2008-2009 global financial crisis and result in dramatically-increased healthcare expenditures; reductions in food and feed production, reduced economic output, and increased poverty and inequality. The economic impact of antimicrobial resistance will be even greater and longer lasting on low-and middle-income (LMIC) countries.
Figure 4. Projected deaths due to antimicrobial resistance in 2050. Source: 2016 O’Neil Report on Tackling Antibiotic Resistance
LMICs
The real implications of spreading drug resistance will be felt the world over, with developing countries and large emerging nations bearing the brunt of this problem.
One-Health Perspective
Because the drivers of antimicrobial resistance lie in humans, animals, plants, food and the environment, a sustained One Health response is essential to engage and unite everyone around a shared vision and goals.
“One Health” refers to designing and implementing programmes, policies, legislation and research in a way that enables multiple sectors engaged in human, terrestrial and aquatic animal and plant health, food and feed production and the environment to communicate and work together to achieve better public health outcomes.
Figure 5. A One Health response to address the drivers and impact of antimicrobial resistance. Source:WHO
Antibiotic use in food production
- 75% if human infectious diseases that have emerged or re-emerged in recent decades are zoonotic-i.e. they originated in animals (Woolhouse and Gowtage-Sequeria 2005).
- Few antimicrobial classes are reserved exclusively for humans- (e.g., isoniazid used for tuberculosis) or drugs limited to veterinary use because of toxicity. The vast majority of antibiotics are used both in humans and animals, including domestic mammals, birds, farmed fish and shellfish, honeybees and others.
- In horticulture, tetracyclines, streptomycin, and other antimicrobials are used for the prophylaxis and treatment of bacterial infections (e.g., fire blight Erwinea amylovora)
- In veterinary medicine, major differences in the way antibiotics are used for companion animals (e.g., dogs, cats, pet birds, horses) versus food-producing animals- Antibiotic use in companion animals is broadly similar to humans to treat clinical infections or in select cases prophylaxis, such as post-surgery.
- In the case of food animals, if some animals are infected antibiotics may be administered through feed or water to the entire group for reasons of practicality or efficiency. Metaphylaxis is a term used to describe therapeutic/prophylaxis treatment at a group level.
- The most controversial type of group treatment in food animals is long-term, low-dose mass antibiotic treatment for purposes of growth promotion. This practice has a high propensity to select to antibiotic microbial resistance and is based on economic grounds rather than treatment of clinical infection.
- The reported benefits of using antibiotics for growth promotion is low and ranges widely in the literature (1-10%). Concerns have been expressed that antimicrobial growth promoters are often used to compensate for poor hygiene/housing and healthy management.
- The WHO has advocated for the termination of using antimicrobials for growth promotion. A recent report from the ECDC has suggested some progress. Using surveillance data from 2017, the report found that the EU/EEA population mean antibiotic consumption in the 29 countries was 130 mg per kg of estimated biomass in humans and 108.3 mg per kg in food-producing animals. This first time since the agencies began publishing the joint reports in 2011 that antibiotic use in humans has exceeded use in livestock. Consumption of third- and fourth-generation cephalosporins, fluoroquinolones, and aminopenicillins was considerably higher in people, while consumption of macrolides was similar, and consumption of tetracyclines and polymyxins—a last-resort class of antibiotics that includes colistin—was significantly higher in food-producing animals.
- In 2022, new EU legislation will prohibit all forms of routine antibiotic use in farming, including preventative group treatments and medicated feeding except in extraordinary circumstances.
Figure 5. Antibiotic use in livestock reported in 2010
Impacts on Human AMR
Case study 1
Third generation cephalosporins (ceftotaxime, ceftriaxone) are widely used for serious infections in humans, including urinary tract, abdominal, lung and bloodstream infections and are classified as “critically-important” for human health (WHO AGISAR). Cetiofur, cefpodoxime, and cefoperazone are 2nd and 3rd generation cephalosporins approved for veterinary use and predominantly for treating bacterial infections in food-producing animals including chickens and cattle.
Resistance to 3rd generation cephalosporins is mediated by extended-spectrum beta-lactamases (ESBLs) and AmpC. ESBL genes are highly mobile and transmitted on plasmids, transposons and other genetic elements horizontally (to surrounding bacteria) and vertically (to daughter cells). Resistance to 3rd generation cephalosporins is common among Escherichia coli and Klebsiella pneumonia requiring greater reliance on the few remaining classes of antimicrobials such as carbapenems.
A number of studies comparing isolates from animals, food and human infections have found a high similarity in ESBL genes and plasmids, as well as similar clonal isolates (Lazarus et al. 2015).
In some countries, ceftiofur was injected in small quantities to many thousands of hatching eggs or chicks intended for treated flocks. The main reason for this treatment is prophylaxis against Escherichia coli infections and/or yolk sac infections.This practice has been shown to select for cephalosporin resistance in Salmonella enterica serovar Heidelberg- an important cause of human illness in many countries that is typically associated with consumption of contaminated poultry products (Smith et al. 2008).
Studies conducted by the Canadian Integrated Program for Antimicrobial Resistance Surveillance detected a high degree of temporal correlation in trends of resistance to ceftiofur (and ceftriaxone, a drug of choice for the treatment of severe cases of salmonellosis in children and pregnant women) among Salmonella Heidelberg from clinical infections in humans, from poultry samples collected at retail stores, and in E. coli from poultry samples collected at retail stores (Canada 2009). Voluntary termination of this use of ceftiofur in hatcheries in the province of Quebec was followed by a precipitous drop in the prevalence of resistance to ceftiofur; subsequent reintroduction of ceftiofur in a more limited way was followed by a return to higher levels of resistance (Figure 7.)
Figure 7. Ceftiofur resistance in chicken and human Salmonella Heidelberg and chicken E. coli.
In Japan, voluntary withdrawal of the off-label use of ceftiofur in hatcheries in 2012 was also followed by a significant decrease in broad-spectrumc ephalosporin resistance in E. coli from chicken prepared for cooking. Some other countries (e.g., Denmark) have also placed voluntary restrictions on its use. The label claim for day-old injection of poultry flocks was withdrawn in Europe, while some countries have banned off-label use of third-generation cephalosporins, and in other countries there is a requirementthat use be restricted to situations where no other effective approved drugs are available for treatment.
The use of cephalosporin antibiotics that are considered critically important for both human and animal health and for which the main concerns for selection and spread of resistance from animals to humans derive from their use as mass medications in large numbers of animals. In this regard,there are parallels with fluoroquinolones, another class of critically important antimicrobials, to which resistance among Campylobacter jejuni isolates emerged following mass medication of poultry flocks (Endtz et al. 1991).
Case study 2
Colistin is a member of the polymixin class of antibiotics, which have been used in both human and veterinary medicine for over 50 years. Until relatively recently, polymixins were rarely used in humans because of dose-limiting neurotoxicity and nephrotoxicity except for topical therapy or inhalational therapy for adjunctive suppression of MDR Pseudomonas aeruginosa in patients with cystic fibrosis.
Intravenous polymyxin is now increasingly used as a drug of last resort for carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. However, colistin continued to be used in Brazil, Europe and China and administered orally in pigs, poultry and calves and for growth promotion in parts of Asia
- In 2014, colistin use in animals was higher than humans with a reported 485 tonnes- 99.7% in oral form or oral medicated feed (Agency 2016). In China, with the world’s largest production of pigs and poultry an estimated 12,000 tonnes of colistin was used in the food production industry (Liu et al. 2016).
- (example of colistin stoppage in Vietman in chickens)
Figure 7. Chicken farm in the United States. Foto credit: The Guardian
Environmental concerns
International spread of AMR
Figure 8. World airline route map 2014